U.S. patent application number 11/154692 was filed with the patent office on 2005-12-29 for minimizing powder retention on surfaces.
This patent application is currently assigned to MEDERIO AG. Invention is credited to Calander, Sven, Kax, Lars, Niemi, Alf.
Application Number | 20050287078 11/154692 |
Document ID | / |
Family ID | 32906844 |
Filed Date | 2005-12-29 |
United States Patent
Application |
20050287078 |
Kind Code |
A1 |
Niemi, Alf ; et al. |
December 29, 2005 |
Minimizing powder retention on surfaces
Abstract
The invention relates to a method for improving the powder
output, i.e. the emitted medication dose, from a dry powder inhaler
device by minimizing the powder retention inside the device. Also
therapeutic efficacy of the metered medication dose is hereby
improved. It is found that adding a smaller amount of excipient
than would be necessary in an ordered mixture, to a metered dose of
an API formulation raises the emitted API dose when the dose is
inhaled together with the excipient.
Inventors: |
Niemi, Alf; (Straengnaes,
SE) ; Calander, Sven; (Strngns, SE) ; Kax,
Lars; (Nykvarn, SE) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
MEDERIO AG
Hergiswil NW
CH
|
Family ID: |
32906844 |
Appl. No.: |
11/154692 |
Filed: |
June 17, 2005 |
Current U.S.
Class: |
424/46 |
Current CPC
Class: |
A61M 2202/064 20130101;
A61M 15/0028 20130101; A61M 11/001 20140204 |
Class at
Publication: |
424/046 |
International
Class: |
A61L 009/04; A61K
009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 2004 |
SE |
0401612-7 |
Claims
We claim:
1. A method of improving an emitted dose of a metered dry powder
medicament dose comprising at least one active pharmaceutical
ingredient from a dry powder inhaler device, comprising: placing a
metered dose of at least one biologically acceptable excipient and
the metered medicament dose in a common space of a dose container
or internal aerosolization chamber in a manner such that the dose
of the medicament and the dose of the excipient are aerosolized
together by the inhaler device during an inhalation, whereby
particles of the excipient dose set particles of the medicament
dose free into a stream of inhalation air, thereby raising an
emitted medicament dose mass and reducing retention of medicament
particles inside the inhaler device, whereby the yield of the
medicament dose increases due to the presence of the excipient dose
as compared to both the absence of the excipient dose and the
presence of the excipient dose in an amount of less than 20:1 wt/wt
excipient/medicament, i.e. excipient's share of medicament and
excipient doses taken together is less than 95%.
2. A composition comprising a metered dose of at least one
biologically acceptable excipient and a metered dry powder
medicament dose, both contained within a common space of a dose
container or internal aerosolization chamber of a dry powder
inhaler device in a manner such that the dose of the medicament and
the dose of the excipient can be aerosolized together by the
inhaler device during an inhalation, whereby particles of the
excipient dose set particles of the medicament dose free into a
stream of inhalation air, thereby raising an emitted medicament
dose mass and reducing retention of medicament particles inside the
inhaler device, whereby the yield of the medicament dose increases
due to the presence of the excipient dose as compared to both the
absence of the excipient dose and the presence of the excipient
dose in an amount of less than 20:1 wt/wt excipient/medicament,
i.e. excipient's share of medicament and excipient doses taken
together is less than 95%.
3. A method for delivering a dose of a metered dry powder
medicament comprising at least one active pharmaceutical ingredient
from a dry powder inhaler device, comprising: inhaling a metered
dose of at least one biologically acceptable excipient and the
metered medicament dose from a common space of a dose container or
internal aerosolization chamber in a manner such that the dose of
the medicament and the dose of the excipient are aerosolized
together, whereby particles of the excipient dose set particles of
the medicament dose free into a stream of inhalation air, thereby
raising an emitted medicament dose mass and reducing retention of
medicament particles inside the inhaler device, whereby the yield
of the medicament dose increases due to the presence of the
excipient dose as compared to both the absence of the excipient
dose and the presence of the excipient dose in an amount of less
than 20:1 wt/wt excipient/medicament, i.e. excipient's share of
medicament and excipient doses taken together is less than 95%,
with optional mixing of the excipient and medicament before and/or
during inhalation.
4. An arrangement in a dry powder inhaler device for improving
emitted dose of a metered dry powder medicament dose, comprising at
least one active pharmaceutical ingredient, when said metered dose
is delivered, wherein a separately metered dose of at least one
biologically acceptable excipient formulation is included with the
metered medicament dose in a common space of a dose container or
internal aerosolization chamber, said excipient dose having a
pre-determined ratio of mass relative the metered medicament dose;
the dose of the medicament and the dose of the excipient are
arranged in the dose container such that said doses become
aerosolized together by the inhaler device during an inhalation,
and whereby particles of the excipient dose set particles of the
medicament dose free into a stream of inhalation air, thereby
raising an emitted medicament dose mass and reducing retention of
medicament particles inside the inhaler device, whereby the yield
of the medicament dose increases due to the presence of the
excipient dose in the dose container.
5. A method of joining a metered, dry powder medication dose,
comprising at least one active pharmaceutical ingredient, together
with a dry powder excipient dose, comprising at least one
biologically acceptable excipient, in a common dose container,
comprising the steps of selecting a formulation of the dry powder
medication dose consisting of inhalable powder particles having a
mass median aerodynamic diameter within a range from about 0.5
.mu.m to about 5 .mu.m; selecting a formulation of the at least one
excipient comprising large particles to at least 90% by mass;
defining an appropriate mass ratio between a selected,
therapeutically effective medication dose mass to be filled and the
dose mass of the excipient, whereupon the corresponding excipient
dose mass is calculated, and metering and filling the selected,
therapeutically effective medication dose and the calculated dose
of the excipient, optionally by making one or more depositions per
dose, into the common dose container.
6. A medical product comprising a dose container enclosing a dry
powder medication dose, comprising at least one active
pharmaceutical ingredient, and further enclosing a dry powder
excipient dose, comprising at least one biologically acceptable
excipient, said doses suitable for inhalation from the dose
container by use of a dry powder inhaler device, wherein the
medication dose has a metered, therapeutically effective mass, said
dose consisting of powder particles of a mass median aerodynamic
diameter in a range from about 0.5 .mu.m to about 5 .mu.m; the
excipient dose has a metered mass calculated from a pre-defined
mass-ratio relative the metered medication dose; said medication
and excipient doses, optionally split up in more deposits than one
per dose in the common dose container, are arranged for a
simultaneous release together upon an inhalation using the dry
powder inhaler device.
Description
REFERENCE TO PRIOR APPLICATIONS
[0001] This application claims the benefit of Swedish application
SE 0401612-7 filed Jun. 18, 2004. U.S. application Ser. No.
10/898,372 filed Jul. 26, 2004, is incorporated herein in its
entirety.
TECHNICAL FIELD
[0002] The present invention relates to the minimization of powder
retention on surfaces. In preferred embodiments the invention
discloses a method and an arrangement for minimizing, for example
in a dry powder inhaler device, retention of a metered dry powder
medicament dose, thereby improving the yield in terms of emitted
dose. In a highly preferred embodiment powder retention is
minimized by adding an excipient dose to the medicament dose,
whereby the excipient assists the release of the medicament dose
during inhalation. In the invention smaller quantities of excipient
are used compared to ordered mixtures according to prior art. In a
further aspect the present invention relates to a method and a
medical product for enclosing a metered, dry powder medication dose
together with a dose of an excipient in a common dose
container.
BACKGROUND
[0003] Within health care today administration of medicaments by
inhalation for distributing dry powder medicaments directly to the
airways and lungs of a user is becoming more and more popular,
because inhalation offers an efficient, fast, and user friendly
delivery of the specific medication substance.
[0004] Dry powder inhalers (DPIs) have become accepted in the
medical service, because they deliver an effective dose in a single
inhalation, they are reliable, often quite small in size and easy
to operate for a user. Two types are common, multi-dose dry powder
inhalers and single dose dry powder inhalers. Multi-dose devices
have the advantage that a quantity of medicament powder, enough for
a large number of doses, is stored inside the inhaler and a dose is
metered from the store shortly before it is supposed to be inhaled.
Single dose inhalers use pre-metered doses and such inhalers are
deposited with a limited number of individually packaged
pre-metered doses, where each dose package or container is opened
shortly before inhalation of the enclosed dose is supposed to take
place.
[0005] Dry powder medicaments may be in a pure formulation
consisting of an active pharmaceutical ingredient (API) only, or
the formulation may comprise other substances for different
purposes, e.g. enhancing agents for increasing the bio-availability
and/or bio-activity of the API. Pharmacologically inert excipients
may be included for diluting a potent API, in order to act as
carrier of the API or to improve the flowability of the formulation
to enhance metering and filling properties of the powder.
[0006] Powders with a particle size suitable for inhalation, i.e.
particles in a range 0.5-5 .mu.m, have a tendency of aggregating,
in other words to form smaller or larger aggregates, which then
have to be de-aggregated before the particles enter into the
airways of the user. De-aggregation is defined as breaking up
aggregated powder by introducing energy e.g. electrical,
mechanical, pneumatic or aerodynamic energy. The aerodynamic
diameter of a particle of any shape is defined as the diameter of a
spherical particle having a density of 1 g/cm.sup.3 that has the
same inertial properties in air as the particle of interest. If
primary particles form aggregates, the aggregates will
aerodynamically behave like one big particle in air.
[0007] The tendency to form aggregates of particles is aggravated
in the presence of water and some powders are sensitive to very
small amounts of water. Under the influence of moisture the formed
aggregates require very high inputs of energy to break up in order
to get the primary particles separated from each other. Another
problem afflicting fine medication powders is electro-static
charging of particles, which leads to difficulties in handling the
powder during dose forming and packaging.
[0008] Methods of dose forming of powder formulations in prior art
include conventional mass, gravimetric or volumetric metering and
devices and machine equipment well known to the pharmaceutical
industry for filling blister packs and gelatin capsules, for
example. See WO 03/66437 A1, WO 03/66436 A1, WO 03/26965 A1, WO
02/44669 A1, DE 100 46 127 A1 and WO 97/41031 for examples of prior
art in volumetric and/or mass methods and devices for producing
metered doses of medicaments in powder form. Electrostatic forming
methods may also be used, for example disclosed in U.S. Pat. No.
6,007,630 and U.S. Pat. No. 5,699,649.
[0009] Gelatin or plastic capsules and blisters made of aluminum or
plastic, or laminates comprising aluminum and plastic foil are
common prior art containers for metered single doses of dry powder
medicaments. Typically, the user has to open the inhaler, insert at
least one container into the inhaler, close it, push a button to
force one or more sharp instrument(s) to penetrate a selected
container, such that the dose may be accessed by streaming air when
the user at leisure decides to inhale the dose. Besides a method of
breaking the container open inside the inhaler and pour out the
dose in a chamber first, the most common methods of opening the
container are to punch one or more holes in the container itself or
in a foil sealing the container or peel off the sealing foil. In
the first case the powder is poured onto a surface inside the
inhaler and made available for inhalation from there. In the second
case the dose is aerosolized by inhalation air being forced through
the container or the dose being shaken out of the container and
immediately aerosolized by streaming air on the outside of the
container.
[0010] Mixtures of API and excipients are very common in the
pharmaceutical industry, particularly for tablets. Drug
formulations containing API(s) and excipient(s) for making tablets
need to be suitable in terms of potency, dosage mass, stability of
form etc. Homogenous mixtures of powders comprising big,
non-inhalable particles are standard in the industry. Such powder
mixtures are easy to handle and make into tablets. However, tablets
don't normally require that the particles of API and/or excipient
ingredients are small enough to be inhalable. Therefore, dry powder
preparations of so-called ordered mixtures of an API formulation of
inhalable particles and an excipient formulation of larger
particles, in some cases also including a small share of micronized
excipient particles, are now common in prior art for inhalable
medicaments. Common reasons for making ordered mixtures are e.g. to
improve flowability of the powder mixture, to let the large
excipient particles act as carriers for the API particles and to
dilute a potent API formulation. Combining these effects is also a
reason for making ordered mixtures. However, the ratio between API
and excipient is limited if a stable, homogenous mixture is to be
achieved, which in a filling process does not segregate small
particles from big ones. The API formulation is limited to 4-5% by
weight (w/w) of the mixture, higher blends gives problems.
Therefore, the total dose mass of an ordered mixture, containing a
therapeutically effective API dose, will often become too big for
pulmonary delivery in a single inhalation.
[0011] Thus, there is still a need for improved efficacy of dry
powder medicament doses in connection with an inhalation process
for the release of a dose of medication powder by a DPI.
SUMMARY
[0012] The present invention relates to the minimization of powder
retention on surfaces.
[0013] The present invention relates in one embodiment to a method
for improving the powder output, i.e. the emitted medication dose,
from a dry powder inhaler device by minimizing the powder retention
inside the device. The therapeutic efficacy of the metered
medication dose is thereby also improved. Surprisingly, we have
found that adding a smaller amount of excipient than would be
necessary in an ordered mixture, to a metered dose of an API
formulation, raises the emitted API dose when the dose is inhaled
together with the excipient.
[0014] In a particular embodiment a dose of an excipient of
approximately the same mass as a therapeutically effective API dose
is filled together with the API dose in a common space of a dose
container. Providing the doses are arranged such that the powders
are aerosolized together upon inhalation, release of the API dose
from the container is improved and retention of API particles in
down stream inhaler channels is reduced, compared to if the
excipient was not present. An inhalable API formulation, which is
sticky and difficult to release and aerosolize by a DPI device,
benefits from having a dose of an excipient of e.g. similar mass
introduced for a joint delivery from the dose container. An
advantage of the present invention is that the total mass of the
accumulated doses is still small enough for an efficient delivery
in a single inhalation from a DPI. If the same mass of API would be
mixed with the excipient into an ordered mixture, the amount of
excipient would have to be 20 times more. The total dose would then
be too big for delivery by a single inhalation. The intended
therapeutic effect would only be reached after multiple
inhalations, if at all. Multiple inhalations put a strain on the
user and increase the risk of incorrect administrations or
non-compliance, whereby the intended therapy is jeopardized.
[0015] According to the invention, the improvement in emitted
medication dose is not influenced by intentional or unintentional
mixing of the doses of API and excipient after filling into the
dose container, as long as the two doses are aerosolized together
during inhalation. In fact, a somewhat random disorder of API and
excipient particles can be an advantage in raising the emitted API
dose figure. Any dry powder formulation for inhalation will benefit
from the invention, such as pure API formulations or formulations
comprising particles consisting of API and other ingredients and
formulations of porous particles e.g. Technospheres.RTM. and
microspheres. The method is particularly useful where the dry
powder formulation in the medication dose is sticky and where
particles of the formulation tend to attach themselves to surfaces
with which they come in contact, such that they are difficult to
set free. The present method may advantageously be applied to
naturally sticky substances and formulations, but also to powders
sensitive to ambient conditions such as elevated temperature and
humidity.
[0016] The present invention also relates to a method for enclosing
1) a metered, dry powder medication dose comprising at least one
active pharmaceutical ingredient (API) and 2) a metered, dry powder
dose of at least one excipient in 3) a common space of a common
dose container. The medication formulation is preferably a dry
powder formulation adapted for inhalation and the excipient or
excipients are preferably biologically acceptable dry powders that
are in all respects compatible with the medication powder. The
invention teaches that the respective formulations are metered and
filled into a common space of the dose container. According to the
invention, the deposited doses in the common dose container
constitute a medical product. The method and the medical product
are effective in raising the emitted medication dose output when
the doses are delivered together by inhalation from a dry powder
inhaler. The therapeutic efficacy of the metered medication dose is
thereby improved.
[0017] In a further aspect of the invention the doses may be
metered and deposited into a common aerosolization chamber inside a
DPI from separate storage chambers or from separate receptacles
inside the DPI in preparation for a delivery by inhalation. The
addition of an excipient dose to a medication dose at the
inhalation stage improves the release of the API of the medication,
such that the emitted medication dose increases and the retention
in the aerosolization chamber and in the down stream airflow
channels decreases. Preferably, the two doses are arranged to be
aerosolized together, simultaneously, e.g. by partly mixing the
doses in the dose container before they are inhaled. The excipient
dose mass is not critical in order to achieve an improved quality
and quantity of the emitted API dose.
DESCRIPTION OF THE DRAWINGS
[0018] The invention will be described in the form of a preferred
and illustrative embodiment and by means of the attached drawings,
wherein like reference numbers indicate like or corresponding
elements and wherein:
[0019] FIG. 1 illustrates in perspective (FIG. 1a), top (FIG. 1b)
and side (FIG. 1c) views a particular embodiment of a sealed dose
container filled with a dose of a medicament and a dose of an
excipient;
[0020] FIG. 2 illustrates a sealed dose container filled with a
dose of a medicament consisting of two deposits and a dose of an
excipient consisting of three deposits;
[0021] FIG. 3 illustrates a sealed dose container after agitation
filled with a dose of a medicament consisting of two deposits and a
dose of an excipient consisting of three deposits where the doses
have become partly mixed;
[0022] FIG. 4 illustrates in a graph results of a climate test
showing the drop in fine particle dose, FPD, of Atrovent.RTM. with
active substance being ipratropium bromide.
[0023] FIG. 5 illustrates in a flow diagram the steps of the
invention for joining a metered medication dose and an excipient
dose in a common dose container.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0024] The present invention relates in a preferred embodiment to a
method for improving the powder output, i.e. the emitted medication
dose, from a dry powder inhaler device by minimizing the powder
retention inside the device. The addition of an excipient dose to a
medication dose helps to release the medication dose, i.e. the API,
and entrain it into inspiration air when the doses are inhaled
together and delivered to a user of a DPI device. Retention of
medication particles inside the DPI is much reduced, not only in
the dose carrier, but also in the downstream air channels, which
direct the airstream carrying the aerosolized medicament dose out
of the DPI and into the users air ways. Retention in the DPI may
result in powder build-ups and may affect the efficacy of the
inhaler adversely. Further, built-up medicament may come loose
during an inhalation, which may result in an overdose to the
user.
[0025] The present invention also teaches a method, illustrated in
a flow diagram in FIG. 5, for joining a metered, dry powder
medication dose and a dry powder dose of a biologically acceptable
excipient in a common dose container. Surprisingly, we have found
that a medical product, based on the present method, improves the
emitted dose, i.e. the output mass of the active ingredient of the
medication powder dose, when the joined doses are inhaled together
from a dry powder inhaler device.
[0026] Surprisingly, we have found that the present invention can
advantageously be applied to many types of dry powder medicament
formulations. Examples of medical dry powders particularly suitable
for the present method include formulations comprising proteins,
including peptides, lipids, water-soluble excipients or APIs,
powders of porous particles, e.g. Technospheres.RTM. and
microspheres. An inhalable API formulation, which otherwise would
be pre-mixed with an excipient into an ordered mixture with the
object of attaining a high degree of efficacy when delivered by
inhalation, can reach the same or even better efficacy and low
retention by applying the teachings of the present invention
instead. The addition of the excipient dose acts as a cleaning
agent and helps to release the medication dose and entrain it into
inspiration air when the doses are inhaled by use of a dry powder
inhaler device. The present invention also offers added benefits by
using only a fraction of the mass of the excipient of an ordered
mixture in order to deliver a therapeutically effective API dose.
The total mass of a therapeutically effective dose of an ordered
mixture is often too big to be suitable for a single act of
inhalation. A high metered dose mass may not become completely
aerosolized by the DPI and too much of the metered dose is then
left unreleased in the dose carrier after an inhalation. The big
amount of excipient in the mixed dose may cause problems for the
user during the inhalation and may trigger coughing spells. The
cumbersome step of producing the ordered mixture is further made
redundant by the present invention, when put to use.
[0027] In a further aspect, it is well known in the art that many
important medicaments in dry powder formulations are sensitive to
high levels of humidity, such that the emitted particle dose out of
an inhaler device drops drastically as the relative humidity in the
air increases. This sensitivity to ambient conditions is especially
noticeable among the new protein-based, inhalable medicaments
currently in development or recently introduced into the
marketplace, e.g. medicaments directed towards treatment of
systemic disorders. In recent years, the pharma industry, having
interests in inhalable medicaments, has directed most development
resources to the formulation side of product development and the
delivery systems, i.e. dose packaging and the inhaler devices, have
been less in focus. Thus, the teachings herein concern improvements
in drug delivery performance by inhalation.
[0028] A highly preferred formulation of an API for inhalation is
preferably chemically and biologically stable under storage and
in-use conditions, and has a high bio-availability and
bio-activity, a suitability for a filling process and a narrow
particle size distribution. There are a number of well-known
techniques for obtaining a suitable primary particle size
distribution that will ensure correct lung deposition for a high
percentage of the dose mass. Such techniques include jet-milling,
spray-drying and super-critical crystallization. There are also a
number of well-known techniques for modifying the forces between
the particles and thereby obtaining a powder with suitable adhesive
forces. Such methods include modification of the shape and surface
properties of the particles, e.g. porous particles and controlled
forming of powder pellets, as well as addition of an inert carrier
with a larger average particle size (so called ordered mixture). A
simpler method of producing a finely divided powder is milling,
which produces crystalline particles, while spray-drying etc
produces generally more amorphous particles. Novel drugs, both for
local and systemic delivery, often include biological
macromolecules, which present completely new demands on the
formulation and the production process. Examples of problems, which
need to be addressed when developing a formulation for inhalation
comprising an API and optionally other substances, are:
[0029] API stability
[0030] Absorption of the API in the lung
[0031] Solubility of the API
[0032] Particle size distribution
[0033] Dilution of API potency
[0034] Elimination of unpleasant taste
[0035] Powder flowability
[0036] When a working formulation of an API has been developed and
regulatorily approved together with a chosen packaging and dose
delivery system, the threshold of improving the formulation
chemically or biologically is very high, because the whole
regulatory process must be repeated. Besides the time and cost
involved in developing a new formulation, most time and money will
be spent on regulatory work. From this aspect, the present
invention may provide a fast road to higher medical efficacy by
making a switch to a different technical platform possible.
Technically, it is very straightforward to implement the present
invention and to switch the packaging and dose delivery systems. A
new dose container may be developed or an existing one may be
chosen capable of accepting a dose of the original API formulation
and a dose of a selected excipient, such that the doses will be
aerosolized simultaneously when made available in a DPI. Examples
of suitable DPIs, which may be used with the present invention are
described in our publications U.S. Pat. No. 6,622,723 and U.S. Pat.
No. 6,422,236. Regulatorily, combining a well-known, proven
formulation with a biologically acceptable excipient does not
require extensive development and clinical studies to aquire an
approval. The regulatory process is normally in such cases
uncomplicated and quick in comparison.
[0037] Dose Forming
[0038] An advantage of the present invention is that prior art
methods of dose forming of medication and excipient powder
formulations for inhalation are easily applied, such as
conventional mass, gravimetric or volumetric dose metering. Filling
devices and machine equipment well known to the pharmaceutical
industry for filling blister packs and gelatin capsules, for
example, may be used. Electrostatic forming methods may also be
used, for example as disclosed in our publication WO 02/11803 (U.S.
Pat. No. 6,696,090) disclosing a method and a process of preparing
a so called electro-powder, suitable for forming doses by an
electro-dynamic method, further described in our publication U.S.
Pat. No. 6,868,853, which both are incorporated hereby in this
document in their entirety by reference. These disclosures stress
the importance of controlling the electrical properties of a
medication powder and points to the problem of moisture in the
powder and the need of low relative humidity in the atmosphere
during dose forming. Ambient conditions during dose metering,
filling and container sealing should be closely controlled. The
ambient temperature is preferably limited to 25.degree. C. maximum
and relative humidity preferably limited to 15% Rh maximum, but the
actual permissible relative humidity depends on the specific
formulation and some cases may require much less than 15% Rh, even
less than 5% Rh. The powder formulation is also to be kept as dry
as possible during the dose forming process. Further, it is very
important to control the electric properties of the powders and to
apply electric charging and discharging as needed, regardless of
which method of dose forming is to be used. Fine powders pick up
static electric charges extremely easily, which can be
advantageously used in dose forming, if the charging and
discharging is under proper control. Keeping the ambient relative
humidity low ensures that only a very small, acceptable amount of
water is enclosed in the dose container together with the dose and
not enough to present a threat to the stability of a moisture
sensitive substance and the fine particle dose (FPD) of the
dose.
[0039] Disregarding which filling method or combination of methods
is preferred, in another embodiment of the invention, a dose
comprising at least one API and a dose comprising at least one
biologically acceptable excipient are separately metered, whereupon
the metered doses are filled together into a dose container,
optionally first being at least partly mixed prior to filling. In a
further particular embodiment, demonstrating the versatility of the
invention in a non-limiting example, a dose of excipient is filled
into the container in a first step, but not spread out inside.
Then, in a second step the medicament is filled into the container,
optionally on top of the excipient. Optionally, a further amount of
excipient is deposited on top of the dose. A further option is to
agitate by e.g. shaking or vibrating the dose container after
filling and optionally after sealing of the container, whereby the
excipient(s) become roughly mixed with the medicament powder.
[0040] Preferably, the de-aggregating system should be as
insensitive as possible to variations in the inhalation effort
produced by the user, such that the delivered aerodynamic particle
size distribution in the inhaled air is largely independent of the
inhalation effort over a certain minimum level. A very high degree
of de-aggregation is generally obtained when one pays attention to
the following:
[0041] a suitable formulation of the powder (particle size
distribution, particle shape, adhesive forces, density, etc)
[0042] a suitably formed dose of the powder adapted to the
capabilities of a selected inhaler device
[0043] an inhaler device providing shear forces of sufficient
strength in the dose to release and de-aggregate the powder (e.g.
turbulence)
[0044] A method and a device for de-aggregating a powder are
disclosed in our U.S. Pat. Nos. 6,840,239 B1 and 6,892,727 B1, the
teachings of which are included in this document by reference.
[0045] Optimized Dose Delivery
[0046] Suitable dose sizes for inhalation are typically in a total
mass range from 1 mg to 20 mg. Smaller doses than 1 mg are
difficult to meter and fill consistently and doses having a mass
exceeding 20 mg may be difficult to release and de-aggregate
completely in a DPI. Many of the new protein-based active
substances require a metered mass of the API in the order of 1-5 mg
to give the desired therapeutic effect when inhaled. If the
medicament comprising the API is a candidate for being included in
a mixture, further comprising an excipient of bigger particles,
typically of average size between 20 and 200 .mu.m, acting as
carriers of the medicament, one must keep in mind that a stable,
homogenous, ordered mixture in bulk quantity that does not begin to
segregate when used in a repetitive filling operation, generally
cannot hold more than 4-5% w/w of the medicament. Segregation means
that small drug particles separate from the big excipient ones,
leading to different concentrations of the API in different parts
of the bulk powder store. Given that the medicament mass is in the
range 1-5 mg, i.e. pure API having a therapeutic effect, a metered
dose of an ordered mixture will be in a range from 20 to 125 mg. A
dose mass in this range is generally not suitable for inhalation.
APIs for systemic absorption by pulmonary delivery should have
aerodynamically very small particles in a range 1-3 .mu.m, which
makes it difficult to make a homogenous, ordered mixture, which
does not segregate when later used in a filling process. If the
concentration of API varies in the bulk powder mixture and if
segregation occurs during handling and in the filling process, it
will be impossible to know how much API drug is filled each time. A
particular aspect of the present invention presents a solution to
this problem by using far less excipient, not in an ordered mixture
with the medicament as in prior art, but separately dosed into the
same dose container or aerosolizing chamber as the medicament dose.
Paradoxically, this method is unknown in prior art. Perhaps the
answer to the paradox is that the focus in the pharmaceutical
industry has been on developing and producing stable drug
formulations, not intended for inhalation, which were easy to mix,
meter and fill industrially using standard methods and equipment.
It is only recently that pharmaceutical companies have started to
look at inhalation as a new method of administration, and have come
to realize that inhalation of drugs means completely new and
different demands on drug formulations.
[0047] The present invention generally uses mass (weight) ratios
API/excipient in a range 1/20-20/1, including endpoints, and all
values and subranges therewithin, for example 1/10-10/1, 1/5-5/1,
1/18, 1/17, 16/1, 12/1, etc. In other words, the excipient dose
mass, according to the disclosure, ranges from 5% to 95% of the
total mass of API and excipient doses taken together, including for
example 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 92%,
93%, 94% and less than 95%. In contrast, in ordered mixtures
typical values are API/excipient in a range from 1/100 to 5/100, in
other words the excipient's share of the total dose mass of an
ordered mixture is typically in a range from 95% to 99%. In fact,
the present invention simplifies the dose filling in many cases,
because the complex process of making a stable mixture of the API
formulation and a suitable excipient is eliminated. For example, a
first dose of the formulation containing the API is metered and
filled into a dose container or aerosolizing chamber and a second
dose of at least one excipient is also filled into the same space
as the first dose in the dose container or chamber. The order of
filling the first and the second doses makes no difference for the
invention, and filling may occur simultaneously as well. In a
particular embodiment each of the respective doses may comprise
more than one powder deposit. Provided the first and second doses
are released simultaneously together upon inhalation, the emitted
dose of the API will be boosted, compared to not having the
excipient dose present in the dose container. In a particular
embodiment the excipient and the API doses have been mixed to some
extent, for example by being agitated, e.g. by vibrating them or by
giving them a physical shock in the container prior to inhalation.
An advantage of the invention is that the road to regulatory
approval may be considerably shorter compared to taking a new
formulation through the necessary, regulatory steps. A further
advantage of the disclosure is that metering and filling of the
medicament dose may become simpler compared to filling an ordered
mixture. Both the cleaning excipient and the medicament are often
easy to meter separately.
[0048] Surprisingly, we have found that even using a small amount
of excipient powder, which is used to coat the inner surfaces of
the container or aerosolization chamber prior to filling of the API
dose, may be sufficient to raise the emitted dose figure of the API
and to reduce the retention of the API inside an inhaler device.
From a filling point of view, however, it is preferred to fill the
container with a first and a second dose of the medicament and the
excipient respectively, in any order or simultaneously, where each
metered dose consists of at least one deposit of the respective dry
powder formulation. Later, when the dose container is opened and
the doses aerosolized during an inhalation, the particles of the
excipient dose act as cleaning agents for the container and the
internal parts of the inhaler, whereby a high share of the
medication powder particles that stick to the interior surfaces
before and during the inhalation are forcibly released, probably by
impaction, and entrained in the streaming inhalation air. The
cleansing effect is very obvious whether or not the medication dose
has been agitated or mixed with the excipient dose after filling
but prior to an inhalation, provided the doses are released
simultaneously together. A possible explanation for this
insensitivity of the invention to the extent of mixing of the
powders in the dose container not limiting of the invention is that
when the doses are released generally simultaneously, large
particles act partly as carriers by picking up small particles and
partly as blasting grit hitting the interior walls of the dose
container and the air channels, whereby many small particles are
released into the airstream. Retention of small medicament
particles is thus reduced.
[0049] Generally, dry powder medicament doses need to be protected
by an enclosure not only during storage, but also when inserted in
an inhaler, e.g. a single dose DPI, where the dose and its
enclosure are kept in a ready state before delivery in an
inhalation at a point in time decided by the user. New types of dry
powder medicaments, not least for systemic treatment, have a rather
short expiry date and they are generally quite sensitive to ambient
conditions, especially moisture during storage and in use. Hence,
the demands put on dose protection and inhaler devices in handling
sensitive doses are therefore much higher than for prior art
devices as used e.g. for administering traditional medicaments
against respiratory disorders.
[0050] In the development of new and improved types of single dose
dry powder inhalers, see our U.S. Pat. Nos. 6,622,723, 6,422,236,
6,868,853, 6,571,793 and 6,840,239, we have also developed dose
filling methods, see our U.S. Pat. No. 6,592,930 and WO 04/110539,
all of which are incorporated in this document in their entirety by
reference. In the development work, particular attention has been
devoted to sticky substances per se. Such dry powders are inclined
to leave a high percentage of the active substance, the active
pharmaceutical ingredient(s), retained on the inner surfaces of the
dose container or aerosolization chamber and on the internal walls
of the air channels inside the inhaler device, through which the
airflow passes carrying the released dose into the airways of the
user. Not surprisingly, if the humidity of the surrounding air is
high, we've found that medical powders in general are inclined to
stick to any surface with which they come in contact. What degree
of air humidity is deemed to be high depends on the sensitivity to
humidity of the powder. The retention effect for a sticky powder
depends, inter alia, on the structure of surfaces in contact with
the powder, the surface areas, the materials concerned, the design
of the inhaler device and the aerosolization and de-aggregation
forces provided by the inhaler, to name a few important factors.
Time is another factor e.g. when stickiness is due to high
moisture. Different powders adsorb more or less humidity and at
different rates. However, many medical powders are affected within
milliseconds of being exposed to humidity in the ambient air. Other
powders adsorb water more slowly. In any case, it is not
satisfactory having an inhaler system designed such that the user
may open a dose container first, allowing the ambient atmosphere
access to the dose therein for an undefined time period of seconds
or even minutes before an inhalation commences.
[0051] In a preferred embodiment of the invention, doses of the
respective formulations of active substance, API, and excipient are
separately metered and filled into the same dose container, where
the doses, intentionally or unintentionally, may or may not be
mixed after filling. However, a nonuniform, random mixture, if
created by shaking for instance, is characterized in that it does
not constitute an ordered mixture, but a nonuniform mixture may be
an optional method of attaining a joint and simultaneous release of
the doses when inhaled. Naturally, the excipient or excipients must
be compatible in all respects with the medication powder. The
improvement in emitted API dose, which follows upon inhalation of
both doses together, as a percentage of the metered API dose is
very significant and the improvement corresponds to a powerful
reduction in retention. Particularly sticky powders may benefit
from the present invention, because the relative improvement in
emitted dose may be more important than for more easily aerosolized
powders. Powders may be naturally sticky or conditionally sticky or
both, e.g. if affected by humidity. A particular embodiment
requires that at least one deposit of the medicament is deposited
in the dose container and that a deposit of the excipient dose is
deposited on each diametrically opposed side of the at least one
medication deposit. The respective deposits of the medicament and
the excipient are preferably of approximately the same mass and the
respective deposits added together constitute the respective
medicament and excipient doses. Typically, the dose mass of the
excipient is roughly the same as the mass of the medication dose,
but other mass ratios may be used. The optimal deposition pattern
of the doses in the dose container, e.g. if doses are split up in
several deposited deposits, depends on how the DPI aerosolizes the
powder in the dose container. In any case, the excipient dose is to
be aerosolized together with the medication dose, but a release
pattern of alternating release of parts of the medication dose
interleaved with release of parts of the excipient dose is equally
possible in order to fully realize the cleaning effect of the
excipient in the course of an inhalation taking place. The coarse
excipient particles may act similarly to a sandblasting device,
i.e. to physically set medicament particles free by sheer impaction
power, but coarse particles also tend to collect small particles
and carry them into the airstream, where the small particles are
released by turbulent forces.
[0052] The excipient may comprise fine particles having sizes
.ltoreq.10 .mu.m, particles .gtoreq.10 .mu.m or the excipient may
comprise fine particles <10 .mu.m and coarse particles >10
.mu.m. The excipient particles having an aerodynamic diameter (AD)
of 10 .mu.m or more are deposited by impaction in the mouth, throat
and upper airways upon inhalation, because the mass of these
excipient particles is generally too big to follow the inspiration
air into the lung. Therefore, excipients are selected inter alia
with consideration for using substances that are harmless when
deposited in the areas concerned. However, an excipient formulation
may comprise more than one excipient. For instance it is often
advantageous to include an excipient containing small particles
.ltoreq.10 .mu.m in a mixture with an excipient containing big
particles .gtoreq.10 .mu.m, more typically .gtoreq.25 .mu.m. This
mixture flows easily and a metered dose of the mixture holds
together when lightly compacted and makes the filling process
simple. The mass ratio between small particles and big ones can be,
e.g., in a range 0.01-0.1 and typically 0.02-0.05 for best
operation. The excipients used may or may not be of the same
substance.
[0053] Suitable excipients for inclusion in a dose container or
chamber include monosaccarides, disaccarides, polylactides, oligo-
and polysaccarides, polyalcohols, polymers, salts or mixtures from
these groups, e.g. glucose, arabinose, lactose, lactose
monohydrate, lactose anhydrous [i.e., no crystalline water present
in lactose molecule], saccharose, maltose, dextrane, sorbitol,
mannitol, xylitol, sodium chloride, calcium carbonate. A particular
excipient is lactose. Lactose in a dry powder form, so called
Respitose.RTM. from DMV International having 95% of particles
larger than 32 .mu.m, has been successfully used as a cleaning
excipient in many inhalation experiments of ours.
[0054] The moisture properties of any proposed excipient should be
checked before it is chosen to be used as a cleaning agent. If an
excipient gives off water, after dose forming, it may negatively
affect the API in the medicament dose, such that the fine particle
dose, FPD, deteriorates rapidly after sealing of the dose
container. Therefore, excipients to be in contact with or mixed
with the medicament are preferably to be selected among acceptable
excipients, which have good moisture properties in the sense that
the excipient will not adversely affect the FPD of the API(s) for
the shelf life of the product, regardless of normal changes in
ambient conditions during transportation and storage. Suitable
"dry" excipients are to be found in the above-mentioned groups. In
a particular embodiment of the present invention, lactose is
selected as the preferred dry excipient and preferably lactose
monohydrate. A reason for selecting lactose as excipient, is its
inherent property of having a low and constant water sorption
isotherm. Excipients having a similar or lower sorption isotherm
can also be considered for use, provided other required qualities
are met.
[0055] The disclosed method counteracts as far as possible any
adverse influence that e.g. humidity in the air may have on the
fine particles in the dose. Minimizing the dose exposure to the
atmosphere may preferably be done by implementing a breath
actuation mechanism coupled to opening of the dose container in the
inhaler. But the present invention may be advantageously used to
boost performance from a dry powder inhaler device. Examples of
problems in prior art dry powder inhaler devices, having negative
effects on the emitted dose are:
[0056] Inhaler design provides too low airflow turbulence close to
dose during inhalation;
[0057] Selected dose container is bigger than necessary and
provides too much internal surface area for powder to stick to;
[0058] Inhaler and dose container present high sticking effects
between dose particles and internal surfaces of dose container and
inhaler;
[0059] User interface of the inhaler gives ambient humid air access
to the dose for a long time before an inhalation actually takes
place;
[0060] Such failings in prior art DPI devices may be rendered less
detrimental and the emitted dose improved by the adoption of the
present invention. Most preferably the present invention is applied
in an inhaler incorporating an Air-razor device for a gradual dose
release in a prolonged dose delivery period, as described in our
U.S. Pat. No. 6,840,239.
EXAMPLE 1
Mixtures of API and Excipient
[0061] In the course of developing methods and products according
to the present invention different APIs were mixed with excipients
in different ratios. The objectives were to find inter alia
suitable formulations and methods of filling doses, but also to
optimize inhaler techniques and interaction between inhaler and
dose container. Table 1 below discloses some examples of
volumetrically dosed mixtures API/excipient and the resulting
emitted dose when delivered by a DPI.
[0062] Conclusions
[0063] As shown in Table 1, mixtures with far more micronized API
(insulin) than 5% were used in these tests. The objective was to
find suitable excipients and to see how different mixing ratios
affected the emitted dose. The mixtures were produced under
laboratory conditions in small quantities and remained quasi-stable
under the run of tests. The emitted dose as percentage of total
recovered dose was measured and the results were used in the
development of the current invention.
1TABLE 1 Emitted Retention Dose in % of in % of Ratio API/
recovered recovered API Excipient Excipient dose dose Micronized
Mannitole 50/50 83 17 insulin Micronized Respitose .RTM. 20/80 93 7
insulin Fluticasone Respitose .RTM. + 10% 1/44 88 12 micronized
lactose
EXAMPLE 2
Ipratropium Climate Stability Tests
[0064] This test was made in order to find out how sensitive
ipratropium bromide is to moisture. Commercially available
Atrovent.RTM. capsules containing ipratropium bromide and excipient
were bought in from our local pharmacy and introduced into the
laboratory together with the HandiHaler.RTM. dry powder inhaler
device. The powder was withdrawn from the originator's capsules and
transferred to the capsules again after climate storage. The
aerodynamic fine particle fraction (FPF) in the emitted dose from
the HandiHaler.RTM. was measured using Andersen impactors according
to European Pharmacopoeia (EP) and US Pharmacopoeia (USP). All
analytical work were then performed according to standardized
methods using a state of the art High Performance Liquid
Chromatograph (HPLC) system.
[0065] Test S1
[0066] Aerodynamic fine particle fraction of metered and delivered
dose out of Handihaler.RTM. using Atrovent.RTM. formulation powder
was analyzed. Transfer of powder from and back into originator
capsules was performed in relative humidity below 10%. The test was
performed with 4 kPa pressure drop over the HandiHaler.RTM. at room
temperature and laboratory ambient conditions.
[0067] Test S2
[0068] An in-use stability test was carried out of the aerodynamic
fine particle fraction of metered and delivered dose out of
Handihaler.RTM.. From the blister holding the Atrovent.RTM.
capsules the powder was transferred to a medium moisture barrier
container and sealed. The containers were put for 1 month in
25.degree. C. and 60% Rh. The container holding the powder was then
put in an exicator for 2 h before tests were performed. The inhaler
test was performed with 4 kPa pressure drop over the
HandiHaler.RTM. at room temperature and laboratory ambient
conditions.
[0069] Test S3
[0070] The same test as in S2 was carried out except that the
containers were put for 1 month in 40.degree. C. and 75% Rh.
[0071] Conclusions
[0072] It is obvious from the graph in FIG. 4 showing the drop in
fine particle dose, FPD, that ipratropium bromide is a very
moisture sensitive substance.
EXAMPLE 3
[0073] In order to illustrate the positive effect on emitted dose,
i.e. the mass of the medicament powder entrained in inspiration air
leaving a typical DPI, the following tests were carried out in our
laboratory.
[0074] A pure, micronized, recombinant, human insulin in dry powder
form was selected as the medicament test substance. Lactose in a
dry powder form, so called Respitose.RTM. from DMV International
having 95% of particles larger than 32 .mu.m, was selected as a
cleaning excipient.
[0075] Four dose containers, aluminum blisters constituting so
called pods, were filled in a dry climate with nominally 2.5 mg
insulin. The filled containers were designated `A`.
[0076] Four further containers, identical to the first four, were
filled in the same, dry climate with nominally 2.5 mg insulin and
2.5 mg Respitose.RTM., in separate filling steps, making a total
dose of 5 mg and a mass ratio of 50/50 between insulin and
Respitose.RTM.. The filled containers were designated `B`.
[0077] The containers were adapted for insertion into a single dose
DPI.
[0078] Two containers of type `A` and two containers of type `B`
were put for an hour before testing in a climate cabinet set at
room temperature and approximately 90% relative humidity and the
remaining containers were stored in the laboratory under normal
ambient conditions.
2TABLE 2 Emitted Dose in Retention % of metered in % of Emitted
Retention, Type of filling dose metered dose dose, .mu.g .mu.g
Ambient `A` 87 13 2166 320 Ambient `B` 93 7 2296 185 Humid `A` 76
24 1982 610 Humid `B` 79 21 1992 543
[0079] The emitted doses were measured using a total of four DPIs,
two per type of filling (`A` and `B`) and climate. Emitted dose was
measured using a HPLC analyzer. Retention in the containers and in
the suction tube and mouthpiece of the inhalers were also measured
using the HPLC analyzer. Results are presented in Table 2
above.
[0080] Conclusions
[0081] The tests show conclusively that the cleaning excipient
Respitos boosts the emitted dose (ED) leaving the inhaler. This is
especially noticable under ambient conditions where the ED
increases from 87 to 93% of the metered dose and retention is
reduced by almost 50% from 13 to 7%. In the humid case the
improvement is significant by 3 percent units, retention is reduced
by approximately 15%, from 24 to 21%. For comparison, an ordered
mixture containing 2.5 mg of insulin API would have a total mass of
at least 50 mg and thus not be suitable for inhalation. It is also
interesting to note that the efficacy of the test DPI system is
very high even under extremely humid conditions.
[0082] The disclosed method is easily adapted to the particular
type of dose container, which has been selected for insertion into
a particular, adapted dry powder inhaler. As already pointed out,
different types of dose containers are advantageously used in the
present invention. Examples of containers are aluminum or plastic
single dose blisters of varying size and design and also capsules
of gelatin, cellulose or plastics. Prior art blister packages for
dry powder medicaments, intended for inhaler use, often have a
fairly thin polymeric seal, which can be easily ripped or punched
open before the dose is supposed to be inhaled. Another common seal
is a peelable foil such that the blister is peeled open prior to
inhalation of the enclosed dose. Yet another type of prior art dose
container is the capsule. Capsules are often made of gelatin, but
polymers and cellulose and other materials are also used. A common
problem for prior art blisters and capsules used for dry powder
doses for inhalation is that the primary package does not protect
sensitive substances from moisture well enough during storage and
in use.
[0083] Using a new type of blister pack, a so-called pod (patent
pending), as a particular embodiment of a sealed dose container, is
to be preferred in an application where the present invention is to
be put to use. A pod container may be made as a high barrier seal
container offering a high level of moisture protection and which is
in itself dry, i.e. it does not contain water. See FIG. 1
illustrating a pod carrying a sealed container in a perspective
drawing. FIG. 1a shows a sealed dose container 33 (seal 31) put
into a protective casing 41 adapted for insertion into a dry powder
inhaler. FIG. 1b shows a top view of the carrier/container and
indicates a dose of a dry powder medicament 22 and a dose of a dry
powder excipient consisting of two deposits 21 inside the container
33 under a seal 31. FIG. 1c illustrates a side view of the
carrier/container in FIG. 1b. FIG. 2 illustrates a similar
container to FIG. 1, but the medicament dose consists of two
deposits 22 and the excipient dose consists of three deposits 21.
FIG. 3 illustrates the dose container in FIG. 2 after agitation of
the container, whereby the deposits 21 and 22 have become partly
mixed in a deposit 23.
[0084] In a further aspect of the invention a dry powder medicament
dose, comprising at least one API, and a dry powder excipient dose,
comprising at least one excipient, may be metered and deposited
together into a common aerosolization chamber in a DPI from
separate storage chambers or from separate receptacles inside the
DPI in preparation for delivery by inhalation. The invention
teaches that the addition of an excipient dose to a medication dose
at the inhalation stage improves the release of the API of the
medication powder dose, such that the emitted API dose increases
and the retention in the aerosolization chamber and in the down
stream airflow channels decreases, compared to if the excipient
dose was not present. The therapeutic efficacy of the metered
medication dose is hereby improved. It is not necessary to arrange
a mixing of the doses, as long as the excipient dose generally is
aerosolized simultaneously with the medication dose. The excipient
dose mass is not critical to achieve an improvement in the quantity
of the emitted API dose. The big excipient particles will impact
and stick in the mouth and throat and become swallowed and will
have no detrimental effect on the efficacy of the emitted dose.
[0085] Preferred embodiments according to the invention
include:
[0086] 1. A method of improving an emitted dose of a metered dry
powder medicament dose comprising at least one active
pharmaceutical ingredient from a dry powder inhaler device,
comprising:
[0087] placing a metered dose of at least one biologically
acceptable excipient and the metered medicament dose in a common
space of a dose container or internal aerosolization chamber in a
manner such that the dose of the medicament and the dose of the
excipient are aerosolized together by the inhaler device during an
inhalation, whereby particles of the excipient dose set particles
of the medicament dose free into a stream of inhalation air,
thereby raising an emitted medicament dose mass and reducing
retention of medicament particles inside the inhaler device,
whereby the yield of the medicament dose increases due to the
presence of the excipient dose as compared to both the absence of
the excipient dose and the presence of the excipient dose in an
amount of less than 20:1 wt/wt excipient/medicament, i.e.
excipient's share of medicament and excipient doses taken together
is less than 95%.
[0088] 2. A composition comprising a metered dose of at least one
biologically acceptable excipient and a metered dry powder
medicament dose, both contained within a common space of a dose
container or internal aerosolization chamber of a dry powder
inhaler device in a manner such that the dose of the medicament and
the dose of the excipient can be aerosolized together by the
inhaler device during an inhalation, whereby particles of the
excipient dose set particles of the medicament dose free into a
stream of inhalation air, thereby raising an emitted medicament
dose mass and reducing retention of medicament particles inside the
inhaler device, whereby the yield of the medicament dose increases
due to the presence of the excipient dose as compared to both the
absence of the excipient dose and the presence of the excipient
dose in an amount of less than 20:1 wt/wt excipient/medicament,
i.e. excipient's share of medicament and excipient doses taken
together is less than 95%.
[0089] 3. A method for delivering a dose of a metered dry powder
medicament comprising at least one active pharmaceutical ingredient
from a dry powder inhaler device, comprising:
[0090] inhaling a metered dose of at least one biologically
acceptable excipient and the metered medicament dose from a common
space of a dose container or internal aerosolization chamber in a
manner such that the dose of the medicament and the dose of the
excipient are aerosolized together, whereby particles of the
excipient dose set particles of the medicament dose free into a
stream of inhalation air, thereby raising an emitted medicament
dose mass and reducing retention of medicament particles inside the
inhaler device, whereby the yield of the medicament dose increases
due to the presence of the excipient dose as compared to both the
absence of the excipient dose and the presence of the excipient
dose in an amount of less than 20:1 wt/wt excipient/medicament,
i.e. excipient's share of medicament and excipient doses taken
together is less than 95%., with optional mixing of the excipient
and medicament before and/or during inhalation.
[0091] 4. The method or composition according to the invention,
where the mass ratio between the medication dose and the excipient
dose is in a range 1:20-20:1.
[0092] 5. The method or composition according to the invention,
where the dry powder medicament comprises, consists essentially of,
or consists of inhalable powder particles having a mass median
aerodynamic diameter within a range from about 0.5 .mu.m to about 5
.mu.m.
[0093] 6. The method or composition according to the invention,
where the excipient is at least one from a group consisting of
monosaccarides, disaccarides, polylactides, oligo- and
polysaccarides, polyalcohols, polymers, salts and mixtures
thereof.
[0094] 7. The method or composition according to the invention,
where the excipient comprises large particles to at least 90% by
mass.
[0095] 8. The method or composition according to the invention,
where the excipient comprises large particles bigger than 20 .mu.m
in size to at least 90% by mass.
[0096] 9. The method according to the invention, comprising the
further step of agitating the dose container enclosing the metered
doses using electrical or mechanical energy such that the doses
inside the container become at least partly mixed, and the mixed
composition produced.
[0097] 10. The method or composition according to the invention,
where the mass ratio between the medication dose and the excipient
dose is in a range 1:10-10:1.
[0098] 11. The method or composition according to the invention,
where the dry powder medicament comprises, consists essentially of,
or consists of inhalable powder particles having a mass (weight)
median aerodynamic diameter within a range from about 0.5 .mu.m to
about 5 .mu.m.
[0099] 12. The method according to embodiment 2, comprising the
further step of
[0100] selecting the at least one excipient from a group consisting
of monosaccarides, disaccarides, polylactides, oligo- and
polysaccarides, polyalcohols, polymers, salts or mixtures
thereof.
[0101] 13. An arrangement in a dry powder inhaler device for
improving emitted dose of a metered dry powder medicament dose,
comprising at least one active pharmaceutical ingredient, when said
metered dose is delivered, wherein
[0102] a separately metered dose of at least one biologically
acceptable excipient formulation is included with the metered
medicament dose in a common space of a dose container or internal
aerosolization chamber, said excipient dose having a pre-determined
ratio of mass relative the metered medicament dose;
[0103] the dose of the medicament and the dose of the excipient are
arranged in the dose container such that said doses become
aerosolized together by the inhaler device during an inhalation,
and
[0104] whereby particles of the excipient dose set particles of the
medicament dose free into a stream of inhalation air, thereby
raising an emitted medicament dose mass and reducing retention of
medicament particles inside the inhaler device, whereby the yield
of the medicament dose increases due to the presence of the
excipient dose in the dose container.
[0105] 14. The arrangement according to the invention, wherein
[0106] the dose container enclosing the metered doses is agitated
using electrical or mechanical energy such that the doses inside
the container become at least partly mixed.
[0107] 15. The arrangement according to the invention, wherein
[0108] a mass ratio between the metered medication dose and the
excipient deposit is selected to be in a range 1:20-20:1.
[0109] 16. The arrangement according to the invention, wherein
[0110] a formulation of the dry powder medicament comprises,
consists essentially of, or consists of inhalable powder particles
having a mass median aerodynamic diameter from about 0.5 .mu.m to
about 5 .mu.m.
[0111] 17. The arrangement according to the invention, wherein
[0112] the excipient is selected from a group consisting of
monosaccarides, disaccarides, polylactides, oligo- and
polysaccarides, polyalcohols, polymers, salts or mixtures
thereof.
[0113] 18. The arrangement according to the invention, wherein
[0114] a formulation is selected of the at least one biologically
acceptable excipient comprising large particles to at least 90% by
mass.
[0115] 19. The arrangement according to the invention, wherein
[0116] a selected formulation of the at least one biologically
acceptable excipient comprises large particles bigger than 20 .mu.m
in size to at least 90% by mass.
[0117] 20. A method of joining a metered, dry powder medication
dose, comprising at least one active pharmaceutical ingredient,
together with a dry powder excipient dose, comprising at least one
biologically acceptable excipient, in a common dose container, said
doses intended for delivery by use of a dry powder inhaler device,
comprising the steps of
[0118] selecting a formulation of the dry powder medication dose
consisting of inhalable powder particles having a mass median
aerodynamic diameter within a range from about 0.5 .mu.m to about 5
.mu.m;
[0119] selecting a formulation of the at least one excipient
comprising large particles to at least 90% by mass;
[0120] defining an appropriate mass ratio between a selected,
therapeutically effective medication dose mass to be filled and the
dose mass of the excipient, whereupon the corresponding excipient
dose mass is calculated, and
[0121] metering and filling the selected, therapeutically effective
medication dose and the calculated dose of the excipient,
optionally by making one or more depositions per dose, into the
common dose container.
[0122] 21. The method according to embodiment 20, comprising the
further step of
[0123] mixing the medication and the excipient doses after an
individual metering operation but prior to depositing the metered
doses into the dose container, whereby the doses are already at
least partly mixed when deposited in said container.
[0124] 22. The method according to embodiment 20, comprising the
further step of agitating the dose container holding the metered
doses using electrical or mechanical energy such that the doses
inside the container become at least partly mixed.
[0125] 23. The method according to embodiment 20 or 21, comprising
the further step of agitating the dose container holding the
metered doses using electrical or mechanical energy such that the
doses inside the container become at least partly mixed.
[0126] 24. The method according to embodiment 20, comprising the
further step of
[0127] selecting the at least one excipient from a group consisting
of monosaccarides, disaccarides, polylactides, oligo- and
polysaccarides, polyalcohols, polymers, salts or mixtures
thereof.
[0128] 25. The method according to embodiment 20, comprising the
further step of
[0129] selecting a formulation of the at least one biologically
acceptable excipient comprising large particles bigger than 20
.mu.m in size to at least 90% by mass.
[0130] 26. The method according to embodiment 24, comprising the
further step of
[0131] selecting a formulation of the at least one biologically
acceptable excipient comprising large particles bigger than 20
.mu.m in size to at least 90% by mass.
[0132] 27. The method according to embodiment 20, comprising the
further step of
[0133] defining the mass ratio between the medication dose and the
excipient dose to be in a range 1:20-20:1.
[0134] 28. The method according to embodiment 20, comprising the
further step of
[0135] sealing the common dose container moisture-tight by using a
high barrier seal.
[0136] 29. A medical product comprising a dose container enclosing
a dry powder medication dose, comprising at least one active
pharmaceutical ingredient, and further enclosing a dry powder
excipient dose, comprising at least one biologically acceptable
excipient, said doses suitable for inhalation from the dose
container by use of a dry powder inhaler device, wherein
[0137] the medication dose has a metered, therapeutically effective
mass, said dose consisting of powder particles of a mass median
aerodynamic diameter in a range from about 0.5 .mu.m to about 5
.mu.m;
[0138] the excipient dose has a metered mass calculated from a
pre-defined mass-ratio relative the metered medication dose;
[0139] said medication and excipient doses, optionally split up in
more deposits than one per dose in the common dose container, are
arranged for a simultaneous release together upon an inhalation
using the dry powder inhaler device.
[0140] 30. The medical product according to embodiment 29, wherein
the dose container holding the metered doses is agitated using
electrical or mechanical energy such that the doses inside the
container become at least partly mixed.
[0141] 31. The medical product according to embodiment 29,
wherein
[0142] a mass ratio between the metered medication dose and the
excipient dose is selected to be in a range 1:20-20:1.
[0143] 32. The medical product according to embodiment 29,
wherein
[0144] the at least one excipient is selected from a group
consisting of monosaccarides, disaccarides, polylactides, oligo-
and polysaccarides, polyalcohols, polymers, salts or mixtures
thereof.
[0145] 33. The medical product according to embodiment 29,
wherein
[0146] the at least one excipient consists to at least 90% by mass
of particles 20 .mu.m in size or bigger and optionally particles of
sizes ranging between 0.5 and 10 .mu.m.
[0147] 34. A use of the medical product according to embodiment 29,
wherein
[0148] an enhanced and consistent delivery of the active
pharmaceutical ingredient of the medication dose is achieved and
retention of the active pharmaceutical ingredient is minimized in
any selected dry powder inhaler device where the medical product is
applied.
[0149] It will be understood by those skilled in the art that
various modifications and changes may be made to the present
invention without departing from the scope thereof, which is
defined by the appended claims.
* * * * *